Biology Reference
In-Depth Information
Strategies for Protein Design
Structural protein design.
The structural approach is the cradle of
protein engineering, marked by a history of more than two decades
of audacious attempts to produce proteins with improved biological
properties. Although not always successful, these engineering experi-
ments thoroughly tested the limits of current QSAR knowledge and
helped identify areas requiring further research. In the medical field,
the attempts centered mainly on the development of new approaches
to vaccines and diagnostic reagents.
The origin of the structural approach can be traced to the first
attempt to model viral antigenic properties with short synthetic pep-
tides. The strategies for chemical synthesis of peptides were developed
at the dawn of the 20th century by chemist Emil Fischer. However, it
was only after 1963, when Bruce Merrifield pioneered his method of
solid-phase peptide synthesis (for which he was awarded the Nobel
Prize almost 20 years later), that the real applications of peptides were
developed in different fields of protein research. In 1963, Anderer
first observed that a short peptide could elicit antibodies immunore-
active with the intact virus.
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These two important advances —
namely, solid-phase peptide synthesis and modeling antigenic epitopes
with short peptides — opened the door for a frontal attack on the
nature of viral antigenic epitopes and the application of this new
knowledge to the design of vaccines and diagnostics. It was not until
more than a decade later, however, that peptide research yielded
important discoveries in this area and the field made an important
next stride toward this goal.
In 1976, Michael Sela, who studied the neutralizing immunore-
sponse to MS2 phage, discovered that a short synthetic peptide, if
properly presented to immunocompetent cells, could elicit a neutral-
izing immunoresponse. This research prompted other studies using
synthetic peptides, which by that time had become available to
researchers in sufficient quantities. Synthetic peptides as short as five
amino acids were found to bind antibodies elicited against a whole
protein (from which the peptides were derived) and to elicit antibod-
ies that specifically recognize this protein.
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